Neisseria gonorrhoeae is an obligate human pathogen that causes the common, sexually-transmitted disease, gonorrhea. Both men and women are susceptible to the disease but women often suffer more signiflcant secondary sequelae, including pelvic Inflammatory disease, endometritis and disseminated infections. Host cell invasion is thought to be a key step in gonococcal infection, potentially facilitating immune escape and trans-epithelial migration into deeper tissues. A few published studies have noted that attachment to and invasion of epithelial cells is enhanced in the presence of an utilizable iron source. However, this observation has not been universally appreciated. Iron replete growth conditions exist in environments in which the gonococcus thrives, namely on human mucosal membranes and within the natural transmission fluid, semen. Moreover, iron sources are readily available within the female genital tract during menses, a stage that has been associated with increased risk for ascending gonococcal infections. Thus, iron replete growth condiflons could potentiate invasion, ascension to the upper genital tract and dissemination. In the studies described in this proposal, we intend to define the role that iron plays in gonococcal invasion of epithelial cells. Specifically, the goals of this application are: to determine the mechanism(s) of iron-induced invasion, to define entry pathways that are employed and to ascertain whether this pathway is important for gonococcal virulence in human and murine models of infection.